Loss of the sense of smell commonly occurs in patients with chronic rhinosinusitis (CRS) and has major impacts on quality of life and patient safety. The pathophysiology behind the olfactory loss observed in CRS is not clearly understood, but animal models suggest that chronic inflammation, a hallmark of CRS, may result in a loss of mature or functional olfactory neurons and an inhibition in olfactory neuron regeneration. CRS results in an influx of inflammatory cells and elevated levels of multiple pro-inflammatory cytokines, including TNF-?, IL-1?, IL-6, IL-17, and IFN-?. These cytokines, in particular, have the potential to negatively modulate neuronal regeneration and the process of neurogenesis, both of which can cause transient or permanent loss of functional neurons. Inhibition of these regenerative pathways is typically mediated through a combination of: 1) effects on neuronal cell migration or differentiation, 2) Inhibition of neuronal progenitor cell proliferation, or 3) induction of neuronal progenitor cell death or apoptosis. The central hypothesis of this proposal is that neurotoxic pro-inflammatory cytokines are overexpressed in CRS and that alteration in cytokine expression and function contributes to CRS-related inflammation and olfactory loss. We will test this hypothesis using human-derived olfactory tissue, including mechanistic studies that directly assess the effect of pro-inflammatory cytokines on olfactory neurons and neuronal progenitor cells. Aim 1 will assess the expression of neurotoxic cytokines in human olfactory tissue and determine whether cytokine expression correlates with objective measures of olfactory function. Aim 2 will determine whether receptors for pro-inflammatory cytokines are expressed on human olfactory neurons and neuronal progenitor cells and will assess the effects of individual cytokines on cellular processes such as proliferation, differentiation, and apoptosis. We hypothesize that pro-inflammatory cytokines, acting through cognate receptors expressed on olfactory neurons and neuronal progenitor cells, negatively modulate olfactory neuron survival and regeneration. Findings from this study will provide insight into the mechanisms of olfactory dysfunction observed in CRS and may help to identify specific therapeutic targets for the selective treatment of CRS-associated olfactory loss.